Ancient epigenetic changes silenced cancer-related genes

An epigenetic change, a form of DNA control, that disables certain cancer-related genes at an advanced stage of human development, has been conserved for over 400 million years, according to new research conducted by the Garvan Institute of Medical Research.

The researchers found that genes activated in some human cancers also exist in zebrafish – but are "silenced" just hours after fertilization. This study sheds new light on how our epigenetics can regulate genes, some of which are related to cancer development later in life over long distances of evolution. It also reveals significant differences between the way the epigenome "resets" in zebrafish and human embryos, which could guide future studies on epigenetic transmission.

"We have shown that we have kept this embryonic event that disables cancer-related genes in humans," says Dr. Ozren Bogdanovic, head of the Epigenomics Development Lab, who led the study. "It's intriguing and we still do not know why this is happening, but it shows how important it is for human health to keep these genes in silence."

The results are published in the journal Nature Communications.

Unexpected parent

At first glance, the man and the zebrafish (a tiny species of South Asian fish) do not seem to be linked: in fact, our common ancestor of evolution dates back more than 400 million years.

But genetically, zebrafish and humans are not that different – we share about 70% of the protein-producing genes. The team led by Garvan began to examine how epigenetic changes, which control the "reading" of DNA, are maintained during embryo development.

The genes are partly controlled by methylation – tags on the DNA that "block" the reading of genes.

The researchers first isolated primordial germ cells, sperm and egg precursor cells, from developing zebrafish embryos and generated bisulfite sequencing data from the Whole genome (WGBS) – a snapshot of all the methylation of DNA in the cell.

The paternal figure of the zebrafish genome

The team has uncovered fundamental differences in DNA methylation in mammalian and zebrafish embryos.

In the human, these DNA methylation labels are usually "swept" when a sperm fertilize an egg, then again methylated again, to ensure the proper development of the egg. embryo. Instead, zebrafish embryos retain the pattern of the father's methyl group.

In this study, the researchers found that the primordial germ cells of the zebrafish did not alter their methylation patterns either, but inherited paternal patterns of DNA methylation. This contrasts with findings in primordial mammalian cells, which undergo a second "deep cleansing" of their DNA methylation labels. The researchers say this discovery sheds light on the molecular principles of germ line development and highlights the zebrafish as a useful experimental model for studying how epigenetic signatures are inherited across generations.

In addition, researchers examined how DNA is methylated in zebrafish embryos at four stages of development. They found 68 methylated and deactivated genes early in embryonic development within 24 hours of fertilization.

"What was interesting, is that most of these genes belong to a group called testicular cancer antigens," says Dr. Ksenia Skvortsova, co-lead author of the study. "Our work shows that it is one of the very first genes" silenced "or targeted by DNA methylation, both in zebrafish and at home. the mammals."

New look at an old mechanism

The genes that code for testicular cancer antigens, or CTAs, are active only in the male testis, but are deactivated in all other tissues, in humans. For some unknown reason, CTA genes are reactivated in some cancers, such as melanomas.

"Mammals and fish have very different strategies for developing an embryo," says Dr. Bogdanovic. "But despite these very different strategies, it appears that CTA's gene control is conserved throughout the evolution."

Although the work shed new light on our evolution, it could have an impact on the future of human health. Drugs that target ACTs are already being studied as a potential cancer treatment. This study provides further evidence of the importance of ACTs and their close control throughout their evolution.

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The authors who contributed to this research come from the Garvan Medical Research Institute, the Institute of Cell Biology (University of Münster), the Harry Perkins Medical Research Institute and the 39, Barcelona Institute of Science and Technology.

Notes to the editor:

Each type of cell in our body, including sperm and egg, has a unique pattern of DNA methylation marks – chemical labels on DNA that regulate the activity of genes.

During the first week after fertilization, humans and other mammals "reset" their DNA methylation patterns, thus allowing the embryo to develop and differentiate into different cell types. Another wave of DNA methylation resetting takes place in primordial germ cells of the embryo, precursors of sperm and oocytes, between the third and seventh week of development in humans . However, it was difficult to determine whether the principles of epigenetic reinitialization are evolutionary and conserved in all vertebrates.